(1) Field of the Invention
This invention relates to a controlled release dosage form for site-specific delivery of therapeutic agents and, more specifically, to a controlled release dosage form for direct transmyocardial delivery of antiarrhythmic agents and methods of making same.
(2) Background of the Prior Art
Life-threatening cardiac arrhythmias are a medical problem confronting millions of persons daily. Arrhythmias are the principal cause of death following myocardial infarction in hundreds of thousands of other persons. Furthermore, cardiac arrhythmias complicate one-third to one-half of the more than three hundred thousand open heart surgeries carried out annually in the United States.
Currently, the millions of persons suffering from cardiac rhythm abnormalities receive oral drug therapy. Examples of frequently prescribed oral antiarrhythmic therapeutic agents are Digitalis, Digitoxin and Procainamide. Other antiarrhythmic agents, such as lidocaine or amiodarone are given intravenously. Conventional drug therapy is often ineffective in either preventing or treating life-threatening ventricular arrhythmias due to inadequate drug concentrations where and/or when needed and adverse side effects of the drugs.
In addition to drug therapy, over one hundred thousand patients per year receive intracardiac electronic pacemakers for severe cardiac rhythm disturbances. However, there are significant problems created with surgical implantation and subsequent maintenance of electronic pacemakers. Recently, ablative surgical and catheterization techniques have been developed to destroy irritable myocardial tissue; but this has not been particularly effective. Accordingly, drug therapy, pacemaker implantation, and surgery are at best only partially effective for preventing and/or suppressing cardiac arrhythmias.
Implantable controlled release drug delivery systems have been investigated in a number of situations in order to achieve site-specific administration and/or prolonged delivery of a therapeutic agent into a particular body component at an effective, but minimal, dosage level in order to reduce the risk of toxic effects of the therapeutic agent. An example of such a system is an implantable infusion pump. Implantable drug delivery systems formulated from polymeric matrices have been developed for, inter alia, preventing infections in in-dwelling devices, such as urinary catheters, by incorporation of antibiotic agents.
The common practice in the prior art, however, is to bond the antibiotic or other drug to a coating on, for example, Dacron polyester or polytetrafluoroethylene (Teflon) materials. Known coatings include gelatin, albumin, graphite-benzalkonium, and cationic surfactants such as tridodecylmethylammonium chloride. In the case of antibiotics, the coatings present a cationic surface which bonds to the anionic antibacterial agent. The antibiotic, however, is rapidly dissipated in the body fluids although a certain amount of antibiotic does remain in the coating until the coating dissipates from the substrate material. Adverse effects, such as toxicity and thrombogenesis, are possible with the use of coatings.
Sustained site-specific cardiac drug delivery has been developed to prevent bacterial endocarditis, to prevent bioprosthetic heart valve calcification and to prevent fibrous tissue buildup. Thyroid and adrenal medulla myocardial autografts were investigated as "endocrinologic cardiac pacemakers." Drug delivery of chronotropic agents has also been accomplished by myocardial implants of silastic reservoirs containing a variety of compounds, including digoxin, isoproterenol, and thyroid hormone, all of which can effectively accelerate cardiac rate when delivered directly into the myocardium.
While these methods have been employed to stimulate and control cardiac rate by transmyocardial drug administration, there have been no examples in the prior art of treatment of ventricular arrhythmias by transmyocardial administration of antiarrhythmic agents.
Moreover, none of the above-described polymeric devices can be fabricated so as to have a particular dosage release characteristic. There are obvious advantages to rapid release of the antiarrhythmic agent immediately post-implantation, followed by slower, sustained release, in the treatment of certain conditions, such as acute arrhythmias.
It is, therefore, an object of the invention to provide biological or synthetic polymeric materials which are compatible with body tissues and which incorporate therapeutic agents, such as antiarrhythmic agents, for the treatment of cardiac rhythm disturbances.
It is a further object of the invention to provide a biocompatible polymeric matrix with incorporated antiarrhythmic agent which can be applied directly to the heart muscle via the epicardium, endocardium, or pericardium.
It is another object of the invention to provide a biocompatible polymeric matrix which incorporates a relatively high concentration of antiarrhythmic agent for site-specific delivery.
It is also an object of the invention to provide a biocompatible polymeric matrix with incorporated antiarrhythmic agent for site-specific delivery of an antiarrhythmic agent such that efficacious results are achieved at body concentrations which are lower than the required plasma level for effectiveness of oral or intravenous administration of such agent.
It is yet another object of the invention to provide a biocompatible polymeric matrix with incorporated antiarrhythmic agent for implantation in, or prolonged contact with, a human or animal body, which has the capability of supplying a high concentration of antiarrhythmic agent directly to the heart muscle, particularly during a critical phase, and of slowly releasing antiarrhythmic agent during an extended period of time thereafter.
It is an additional object of the invention to provide a technique for fabricating a biocompatible polymeric matrix with incorporated antiarrhythmic agent wherein the release characteristics of the antiarrhythmic agent can be selectably varied.
It is additionally an object of this invention to provide a biocompatible polymeric matrix with incorporated antiarrhythmic agent which eliminates or minimizes the side effects of antiarrhythmic agents yet optimizes the beneficial effects of these agents.
It is yet a further object of this invention to provide a more effective method of treatment of arrhythmia than current techniques such as oral or intravenous drug administration, cardiac pacemaker implantation, or surgical removal or destruction of irritable heart tissue.